Diphosphonoalkane carboxylic acids, process of preparation and methods of use

ABSTRACT

Diphosphonoalkane carboxylic acids having the formula ##STR1## wherein R is H or --CH 2  --CH 2  --COOH; as well as their water-soluble salts. The compounds are excellent sequestering agents, especially for alkaline earth and earth metal ions. They are stabilizers for percompounds and are useful in the delaying of the setting times for gypsum. In addition, the compounds are useful in cosmetic preparations, such as toothpastes and mouthwashes where they prevent formation of tartar and plaque and are useful in therapy in the treatment of diseases related to the abnormal deposition or dissolution of difficultly soluble calcium salts in the animal body.

This is a division of Ser. No. 761,271, filed Jan. 21, 1977, now U.S.Pat. No. 4,077,997.

THE RELATED ART

Compounds of the oligocarboxylic alkane phosphonic acids type havegained in importance in recent times owing to their sequestering action.Compounds of this type are used as builder substances in cleaningagents, a substantial advantage residing in their satisfactory hardnessstabilization with small dosages, particularly in the cleaning ofcontainers and bottles. 2-phosphono-butane-1,2,4-tricarboxylic acid and3-phosphono-pentane-1,3,5-tricarboxylic acid have proved to beparticularly suitable in practice.

OBJECTS OF THE INVENTION

An object of the present invention is the obtaining of adiphosphonoalkane carboxylic acid selected from the group consisting of(A) a compound of the formula ##STR2## wherein R is selected from thegroup consisting of hydrogen and --CH₂ --CH₂ --COOH, and (B) anon-toxic, pharmacologically acceptable water-soluble salt thereof.

Another object of the present invention is the development of a processfor the production of the above diphosphonoalkane carboxylic acid byreacting an ester of methylene diphosphonic acid with an ester ofacrylic acid under alkaline conditions and hydrolyzing the resultantester of diphosphonoalkane carboxylic acid.

A further object of the present invention is the development of aprocess for the delaying or inhibiting of the precipitation of alkalineearth metal ions from solution by the use of stoichiometric tosub-stoichiometric amounts of the above diphosphonoalkane carboxylicacids or their water-soluble salts.

These and other objects of the present invention will become moreapparent as the description thereof proceeds.

DESCRIPTION OF THE INVENTION

The subject of the invention is new diphosphonoalkane carboxylic acidsand water-soluble salts thereof. The said compounds are good complexformers and have further valuable properties with respect to theirtechnical use.

Unexpectedly, it was found that the new diphosphonoalkane carboxylicacids described hereinafter have considerably better properties than theoligocarboxylic alkane phosphonic acids described by the prior art.

The new diphosphonoalkane carboxylic acids correspond to Formula I:##STR3## in which R = --H or represents --CH₂ --CH₂ --COOH, as well astheir water-soluble salts. More particularly the present inventionrelates to a diphosphonoalkane carboxylic acid selected from the groupconsisting of (A) a compound of the formula ##STR4## wherein R isselected from the group consisting of hydrogen and --CH₂ --CH₂ --COOH,and (B) a non-toxic, pharmacologically acceptable water-soluble saltthereof.

Compounds of the Formula I, in which R = --H, can be produced byreacting an acrylic acid ester with a methylene diphosphonic acid esterin the molar ratio of 1:1 in the presence of basic catalysts, such as,in particular, alkali metal lower alkanolates. The reaction product isthen converted to the desired acid by saponification.

Diphosphonoalkane carboxylic acids of the Formula I, in which R = --CH₂--CH₂ --COOH, are obtained in a similar manner by reacting an acrylicacid ester with a methylene diphosphonic acid ester in the molar ratioof at least 2:1 in the presence of basic catalysts, and subsequentlysaponifying the reaction product.

More particularly then, the processes are, respectively, a process forthe production of the diphosphonoalkane carboxylic acid of Formula Iwherein R is hydrogen, consisting essentially of reacting a lower alkylester of acrylic acid with a lower alkyl ester of methylenediphosphonicacid in a 1:1 molar ratio in the presence of a strong basic catalyst,saponifying the reaction product under aqueous acidic saponificationconditions and recovering said diphosphonoalkane carboxylic acid where Ris hydrogen, and a process for the production of the diphosphonoalkanecarboxylic acid of Formula I, wherein R is --CH₂ --CH₂ --COOH,consisting essentially of reacting a lower alkyl ester of acrylic acidwith a lower alkyl ester of methylene diphosphonic acid in at least a2:1 molar ratio in the presence of a strongly basic catalyst,saponifying the reaction product under aqueous acidic saponificationconditions and recovering said diphosphonoalkane carboxylic acid where Ris --CH₂ --CH₂ --COOH.

The reactions are preferably conducted in the presence of a saturatedsolution of an alkali metal lower alkanolate in a lower alkanol, such asCH₃ ONa/CH₃ OH at an elevated temperature (due to the exothermicreaction). The saponification is preferably conducted in a heated acidicaqueous solution, such as refluxing concentrated hydrochloric acid.

The phosphonic acids described above can be converted to thecorresponding non-toxic, pharmacologically acceptable, water-solublesalts by complete or partial neutralization with inorganic, organic orquaternary bases, such as alkali metal hydroxide, for example, NaOH,KOH, LiOH; alkali metal carbonates, such as Na₂ CO₃ ; NH₄ OH; loweralkylamines, such as methylamine; lower alkanolamines, such asmonoethanolamine, diethanolamine, triethanolamine; andtetra-lower-alkyl-ammonium hydroxides, such as tetramethyl-ammoniumhydroxide.

The new diphosphonoalkane carboxylic acids, including their alkalimetal, ammonium or alkanolamine salts, are satisfactory complex formersfor alkaline earth ions, preferably calcium ions, and can, therefore, bespecifically used for water softening operations. It is unnecessary towork with stoichiometric quantities, and calcite precipitations can beconsiderably delayed by using sub-stoichiometric quantities.

Thus, they are eminently suitable as anti-corrosion and anti-scalingagents for cooling water, particularly combined with known additives,such as bivalent zinc and/or cadmium salts, orthophosphates, chromatesor hydrazine hydrate.

The amount which is to be regarded as stoichiometric according to thecompound which is used can be readily determined by a simple test.Theoretically, 1 mol of the compound should sequester up to 2 mols ofcalcium ions. In general, the complex formers are used in quantities offrom 1 mol per 2,000 mols of metal ions up to six times thestoichiometric quantity.

Owing to the said properties, the new complex formers can also be used,for example, for the descaling of fabrics in which alkali salts havebeen deposited, and to reduce the ash concentration in fabrics.Furthermore, they are suitable for processes for cleaning rigid articlessuch as metal or glass. Their use as additive to bottle-rinsing agentsis particularly important.

Advantageously, the complex forming capacity can also be used in systemsin which copper ions have an undesirable influence. Examples of thiswhich may be mentioned are the avoidance of the decomposition ofpercompounds or, alternatively, the stabilization of fats and soaps.Furthermore, the said compounds are suitable for use as additives todyeing baths for textiles in order to bind, in a complex manner, thosemetal ions which form undesirable tints.

Finally, the complex forming capacity can also be used to feed so-calledtrace elements to plants. The satisfactory complex forming capacity ofthese compounds is also exhibited by the fact that the known red color,which is otherwise observed when adding rhodanide to solutions whichcontain tervalent iron, does not occur. Thus, these properties can alsobe used in an advantageous manner in order to prevent the depositing ofiron compounds, particularly iron hydroxide, on fabrics or when washingbottles. The new compounds can also be used in galvanic baths instead ofcyanides.

Finally, they are also suitable as builder substances with complexingproperties in washing and cleaning agents and can be used in combinationwith known anionic, cationic or non-ionic, surface-active compounds.Furthermore, they can be used in combination with caustic alkalies,alkali metal carbonates, alkali metal silicates, alkali metalphosphonates, or alkali metal borates.

The diphosphonic acids which have been described are also suitable asactive substances in pharmaceutical or cosmetic preparations which areused for the therapeutic or prophylactic treatment of disorders in thecalcium or phosphate metabolism and the associated diseases. Thesediseases can be divided into two categories:

1. Abnormal depositions of difficultly soluble calcium salts, mostlycalcium phosphate, cause bone malformations, pathological hardening oftissues and secretions in organs.

2. The abnormal dissolution of hard tissues causes losses of hard bonesubstance, which cannot be replaced or are replaced only by incompletelycrystallized tissue. This dissolution is frequently accompanied bypathologically high calcium and phosphate concentrations in the plasma.

These diseases include: osteoporosis, osteodystrophy, Paget's disease,myositis ossificans, Bechterew's disease, cholelithiasis,nephrolithiasis, urinary calculus, hardening of the arteries(sclerosis), arthritis, bursitis, neuritis, tetany.

Instead of the free acids, their non-toxic pharmacologically acceptablesalts, such as sodium, potassium, magnesium, ammonium and substitutedammonium salts, such as mono-, di or triethanol ammonium salts, aresuitable for pharmaceutical use. The partial salts, in which only aportion of the acid protons is replaced by other cations, can be used aswell as full salts, although partial salts, which react substantiallyneutral in aqueous solution (pH 5 to 9) are preferred. Mixtures of theaforesaid salts may also be used.

The dosage of the compounds used is variable and depends upon theprevailing conditions, such as the nature and the seriousness of thedisease, the duration of the treatment and the particular compound.Individual doses can be from 0.05 to 500 mg per kg of body weight. Thepreferred dosage is 1 to 50 mg per kg of body weight per day and can beadministered in up to four doses daily. Owing to the limited resorption,the higher dosages are required in the case of oral application. In thecase of treatment over a long period of time, smaller doses arenecessary after high initial doses in order to maintain the desiredeffect.

Doses of less than 0.05 mg/kg of body weight do not have any significanteffect upon the pathological calcification or the resolution ofcalcified tissues. Long-term toxic side effects can occur in the case ofdoses in excess of 500 mg/kg of body weight. The described diphosphonicacids or their salts may be administered orally in the form of tabletsor capsules, as well as subcutaneously, intramuscularly or intravenouslyin hypertonic solution. The preferred dosage ranges for these uses are(in mg/kg per day):

Orally -- 1.0 to 50.0

Subcutaneously -- 1.0 to 10.0

Intramuscularly -- 0.05 to 10.0

Intravenously -- 0.05 to 2.0

The substances can be formulated for administration in the form oftablets, pills, capsules or injection solutions.

They can be used in combination with the hormone calcitonine for thetreatment of disorders of calcium or phosphate metabolism. Suitablecalcitonines are synthetic and natural calcitonine obtained from pigs,cattle and salmon. It is also possible to use calcitonines whosebiological efficacy has been changed by the substitution of individualamino acid groups in the peptide chain of the natural calcitonines whichcomprise 32 amino acids. Some of these calcitonines which have beenmentioned are commercially available.

In the case of animals, the substances can also be used in fodder and asfodder additives.

When used in cosmetic preparations, such as mouthwashes and toothpastes,the diphosphonic acids in accordance with the invention or theirpharmacologically harmless salts in concentrations of 0.01% to 5% byweight, prevent the formation of tartar or plaque.

Finally, the new diphosphonic acids are also suitable as an additive topreparations for producing 99^(m) technetium radio diagonstics. Diseasesof the bones and tissues can be recognized and localized by radiography.The isotope technetium 99^(m), which has a half-life period of 6 hours,has been used for this purpose in recent times.

Convenient devices are available for its production, from which theradioactive isotope in the form of 99^(m) pertechnetate can be obtainedby elution with an isotonic solution of common salt.

Pertechnetate 99^(m) differs from the radioactive fluorine or strontiumpreviously used in that it does not combine specifically in the skeletonor in calciferous tumors in the body. It has to be reduced to a lowoxidation stage for use and then has to be stabilized in this oxidationstage by means of a suitable complex former.

Furthermore, the complex former must have a high selectivity for thepreferred absorption by the skeleton or by calciferous tumors.

It has been discovered that the complexing diphosphonic acids describedabove, or pharmaceutically harmless water-soluble salts thereof, areparticularly suitable for these purposes. The phosphonic acids are usedtogether with a pharmaceutically acceptable tin (II), chromium (II) oriron (II) salt, the reducing salts being present in stoichiometricsubordinate quantities relative to the phosphonic acids or water-solublesalts thereof. Thus, it is possible to produce, in a simple manner, ahighly stable product which is suitable for sale in a solid form astablets or in the form of a solution contained in an ampoule.

After the diphosphonic acid/reduced metal salt preparation has beenadded to a pertechnetate solution, the resultant complex forms a veryeffective means for diagnosing bone tumors, local disorders in bonemetabolism and calciferous tissue tumors.

The present invention will now be further described by means of thefollowing examples, which are not limitative in any manner.

EXAMPLE 1

57.6 gm (0.2 mol) of tetraethyl methylenediphosphonate and 34.4 gm (0.4mol) of methyl acrylate were mixed and 12 to 14 ml of freshly preparedsaturated CH₃ ONa/CH₃ OH solution were added drop by drop underagitation. The reaction temperature reached 90° C. Agitation wascontinued for two hours at 90° C. to 100° C. after the exothermicreaction had ceased. The reaction product was then subject to vacuumfractionation. The main fraction of the ester obtained had a boilingpoint of 210° C. to 216° C./0.09 Torr. The density n_(D) ²⁰ was 1.4513.The yield was 88%.

The ester obtained was subsequently saponified be refluxing for a longperiod of time with concentrated hydrochloric acid and the free acid wasseparated. The yield upon saponification was approximately 86%. Inaccordance with potentiometric titration, the diphosphonoalkanedicarboxylic acid of the formula ##STR5## (I, R = --CH₂ --CH₂ --COOH)which was obtained had a molecular weight of 330 (Calculated 320).

Analysis Values: Calculated: C 26.25% H 4.36% P 19.38%. Found: C 26.31%H 4.72% P 18.67%.

EXAMPLE 2

57.6 gm (0.2 mol) of tetraethyl methylenediphosphonate and 17.2 gm (0.2mol) of methyl acrylate were mixed, and 10 ml of saturated sodiumethanolate solution were added drop by drop under agitation. Thereaction temperature increased to 60° C. The additive reaction wascompleted by postheating to 80° C. to 90° C. for 2 1/2 hours.

The reaction product was subject to vacuum fractionation. The mainfraction of the ester obtained had a boiling point of 180° C. to 188°C./0.4 Torr and a density of n_(D) ²⁰ = 1,4510. The yield was 33%.

The ester obtained was subsequently saponified by refluxing for a longperiod of time with concentrated hydrochloric acid and the free acid wasseparated. The yield upon saponification was approximately 87%. Inaccordance with potentiometric titration, the molecular weight of the1,1-diphosphonopropane-3-carboxylic acid of the formula ##STR6## (I, R =H), obtained in the form of dihydrate, was 280.3 (calculated 284).

Analysis Values: Calculated C 16.90% H 4.93% P 21.83%. Found C 17.16% H4.90% P 21.06%.

EXAMPLE 3

The acids of Examples 1 and 2 in aqueous solution were mixed with thestoichiometric amount of sodium hydroxide solution and evaporated todryness to obtain, respectively:

Hexasodium 3,3-diphosphonate-pentane-1,5-dicarboxylate and

Pentasodium 1,1-diphosphonate-propane-3-carboxylate.

EXAMPLE 4 Threshold Effect -- Modified Hampshire Test

The determining of the complex binding capacity by means of the modifiedHampshire test, that is, the dissolving of freshly precipitated CaCO₃,clearly shows the efficacy of the new complex formers(III and IV).

The compounds I to IV utilized in the test were the following:

I 2-phosphono-butane-1,2,4-tricarboxylic acid

Ii 3-phosphono-pentane-1,3,5-tricarboxylic acid

Iii 3,3-diphosphono-pentane-1,5-dicarboxylic acid

Iv 1,1-diphosphono-propane-3-carboxylic acid.

200 mgm of the sequestering agent were dissolved in 10 ml of H₂ O (whichhas been adjusted with NaOH to pHll); and 100 ml of sodium carbonatesolution (14.3 gm of Na₂ CO₃ . H₂ O/liter) were added. A calciumsolution (36.8 gm of CaCl₂ . 2H₂ O/liter) was added dropwise from aburette until the cloudiness formed barely remains. The results aregiven in Table I.

                  TABLE I                                                         ______________________________________                                                         MHT Values at pH 11                                          Complex Former   in gm-ions of Ca/Mol Acid                                    ______________________________________                                        I                1.60                                                         II               1.26                                                         III              2.91                                                         IV               2.20                                                         ______________________________________                                    

EXAMPLE 5 Threshold Effect -- Carbonate/Silicate Test

The hardness-stabilizing effect in sub-stoichiometric quantities wasdetermined at 60° C. and 95° C. in a sodium carbonate-silicate buildersubstance formulation.

25 ml of water having a German hardness of 80° C. (Ca:Mg = 4:1) in a 100ml graduated cylinder were treated with the sequestering agent solution(7.5 mgm or 15.0 mgm). After dilution with distilled water up to avolume of 65 to 70 ml, 25 ml of a sodium carbonate-sodium silicatesolution having a concentration of 4.5 gm of Na₂ CO₃ /liter and 600 mgmof sodium silicate/liter (in a ratio of SiO₂ :Na₂ O = 3.36:1) were addedAfter filling up to the 100 ml mark, the sample was either heated to 60°C. within 20 minutes and maintained at this temperature for anadditional ten minutes (see Table II for the results of this procedure);or the sample was heated to 95° C. within 25 to 30 minutes andmaintained at 95° C. for an additional 30 minutes. (See Table III forthe results of this procedure).

Subsequently, the solution, the precipitated portion, and theincrustation tightly adhering to the glass were analyzed as to theircalcium content. In Table II and Table III, the results of the analysesare expressed in percent whereby the sum of the resulting values is setequal to 100%. The compounds employed are identified above in Example 4.

                  TABLE II                                                        ______________________________________                                        150 mg/liter - 60° C                                                   Complex   % CaO      % CaO      % CaO                                         Former    Dissolved  Precipitated                                                                             Incrustation                                  ______________________________________                                        I         98.8       1.0        0.2                                           II        27.4       54.7       17.9                                          III       100.0      0          0                                             IV        100.0      0          0                                             ______________________________________                                    

                  TABLE III                                                       ______________________________________                                        150 mg/liter - 95° C                                                   Complex   % CaO      % CaO      % CaO                                         Former    Dissolved  Precipitated                                                                             Incrustation                                  ______________________________________                                        I         98.9       0.9        0.2                                           II        6.1        4.4        89.5                                          III       100.0      0          0                                             IV        98.0       2.0        0                                             ______________________________________                                    

Compounds III and IV are in accordance with the invention

EXAMPLE 6 Pharmaceutical Preparations

For the production of pharmaceutical preparations in the form of atablet, the known methods of preparation were followed to produce atablet having an effective dosage unit composition as follows:

Compound of Example 1 -- 100 mgm

Lactose -- 100 mgm

Starch -- 47 mgm

Magnesium stearate -- 3 mgm

For the production of pharamceutical preparations in the form of acapsule, the known methods of preparation are followed to produce acapsule having an effective dosage unit composition as follows:

Compound of Example 2 -- 100 mgm

Starch -- 20 mgm

Sodium lauryl sulfate -- 1 mgm

The compounds of the invention are interchangeable in the aboveformulations. In another series of compositions, the free acids in theabove formulations were replaced by the corresponding amounts of thetetrasodium or trisodium salts of the acids, respectively.

EXAMPLE 7 Cosmetic Preparations

The following recipes are suitable as a basic formula for toothpastes:

    ______________________________________                                                                Parts by                                                                      Weight                                                ______________________________________                                        (a)    Glycerin               60.0                                                   Water                  13.5                                                   Sodium carboxymethyl-cellulose                                                                       0.6                                                    Silicic acid zerogel   20.0                                                   Sodium laurylsulfate   2.0                                                    Essential oils         1.0                                                    Sweetening agent       0.4                                                    Compound of Example 2  2.5                                             (b)    Glycerin               30.0                                                   Water                  18.5                                                   Sodium carboxymethyl-cellulose                                                                       1.0                                                    Aluminum hydroxide     44.0                                                   Sodium laurylsulfate   1.0                                                    Pyrogenic silicic acid 1.5                                                    Essential oils         1.5                                                    Sweetening agent       0.5                                                    Compound of Example 1  2.0                                             ______________________________________                                    

Suitable as a basic formulation for mouthwashes is the following recipe:

    ______________________________________                                                             Parts by                                                                      Weight                                                   ______________________________________                                        Ethyl alcohol          19.5                                                   Glycerin               7.5                                                    Water                  70.0                                                   Essential oils         0.2                                                    Sodium laurylsulfate   0.1                                                    Antiseptic (chlorothymol)                                                                            0.1                                                    Sweetening agent       0.1                                                    Compound of Example 2  2.5                                                    ______________________________________                                    

The corresponding neutral salts such as the sodium salts can also beemployed.

By regular use of the mouthwashes and/or toothpastes containing theabove-mentioned diphosphonoalkane carboxylic acids, according to theinvention, the formation of tartar could be considerably reduced. Theformation of hard compact plaque on the teeth was to a great extentprevented.

The preceding specific embodiments are illustrative of the practice ofthe invention. It is to be understood, however, that other expedientsknown to those skilled in the art or discussed herein may be employedwithout departing from the spirit of the invention or the scope of theappended claims.

We claim:
 1. A diphosphonoalkane carboxylic acid selected from the groupconsisting of (A) a compound of the formula ##STR7## and (B) anon-toxic, pharmacologically acceptable water-soluble salt thereof.
 2. Aprocess for the production of diphosphonoalkane carboxylic acid of claim1, consisting essentially of reacting a lower alkyl ester of acrylicacid with a lower alkyl ester of methylenediphosphonic acid in a 1:1molar ratio in the presence of a strongly basic catalyst, saponifyingthe reaction product under aqueous acidic saponification conditions andrecovering said diphosphonoalkane carboxylic acid.